Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n ‫؍‬ 253 total) and healthy newborn controls (n ‫؍‬ 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C3 T) and 1,298 (A3 C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL؉, n ‫؍‬ 37) when compared with controls [adjusted odd ratios (OR) ‫؍‬ 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P ‫؍‬ 0.017]. This protective effect was not evident for A1298C alleles (OR ‫؍‬ 1.14). In contrast, associations for A1298C homozygotes (CC; OR ‫؍‬ 0.26 with a 95% CI of 0.07-0.81) and C677T homozygotes (TT; OR ‫؍‬ 0.49 with a 95% CI of 0.20 -1.17) were observed for hyperdiploid leukemias (n ‫؍‬ 138). No significant associations were evident for either polymorphism with TEL-AML1؉ leukemias (n ‫؍‬ 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

The association between tumor EpsteinBarr virus (EBV) status and clinical outcome in Hodgkin lymphoma (HL) is controversial. This population-based study assessed the impact of EBV status on survival in age-stratified cohorts of adults with classic HL (cHL). Data from 437 cases were analyzed with a median follow-up of 93 months. Overall survival (OS) was significantly better for EBVnegative compared with EBV-positive patients (P < .001), with 5-year survival rates of 81% and 66%, respectively; diseasespecific survival (DSS) was also greater for EBV-negative patients (P ‫؍‬ .03). The impact of EBV status varied with age at diagnosis. In patients aged 16 to 34 years, EBV-associated cases had a survival advantage compared with EBV-negative cases, but differences were not statistically significant (P ‫؍‬ .21). Among patients 50 years or older, EBV positivity was associated with a significantly poorer outcome (P ‫؍‬ .

A UK population-based case–control study of Hodgkin's disease (HD) in young adults (16–24 years) included 118 cases and 237 controls matched on year of birth, gender and county of residence. The majority (103) of the cases were classified by Epstein–Barr virus (EBV) status (EBV present in Reed–Stenberg cells), with 19 being EBV-positive. Analyses using conditional logistic regression are presented of subject reports of prior infectious disease (infectious mononucleosis (IM), chicken pox, measles, mumps, pertussis and rubella). In these analyses HD cases are compared with matched controls, EBV-positive cases and EBV-negative cases are compared separately with their controls and formal tests of differences of association by EBV status are applied. A prior history of IM was positively associated with HD (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.10–5.33) and with EBV-positive HD (OR = 9.16, 95% CI = 1.07–78.31) and the difference between EBV-positive and EBV-negative HD was statistically significant (P = 0.013). The remaining infectious illnesses (combined) were negatively associated with HD, EBV-positive HD and EBV-negative HD (in the total series, for ≥2 episodes compared with ≤1, OR = 0.45, 95% CI = 0.25–0.83). These results support previous evidence that early exposure to infection protects against HD and that IM increases subsequent risk; the comparisons of EBV-positive and EBV-negative HD are new and generate hypotheses for further study. © 2000 Cancer ResearchCampaign

A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBVrelated HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.case series | epidemiology

Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio [OR] = 0.81, 95% confidence interval [95% CI] = 0.76–0.86, Pcombined = 3.5 × 10−10), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16.1, 5q31, 6p31.2, 8q24.21 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk

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To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space -time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space -time interactions between cases were applied with fixed thresholds of close in space, 55 km, and close in time, 51 year apart. Addresses at birth and diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. Tests for heterogeneity and Edwards' test for sinusoidal variation were applied to examine changes of incidence with month of birth or diagnosis. There was strong evidence of space -time clustering, particularly involving cases of astrocytoma and ependymoma. Analyses of seasonal variation showed excesses of cases born in the late Autumn or Winter. Results are consistent with a role for infections in a proportion of cases from these diagnostic groups. Further studies are needed to identify putative infectious agents. British Journal of Cancer (2002) In the developed world central nervous system (CNS) tumours are the second most common group of malignancies in children (Parkin et al, 1998). The aetiology of childhood CNS tumours is far from clear. Heritable syndromes are the only established causes, but these account for a minority of cases (Bondy et al, 1991). A number of statistically significant associations with certain exposures have been noted from case -control studies, including: consumption of cured meats/fish during pregnancy; insecticides/pesticides; farm residence; and electro-magnetic fields (Little, 1999). However, there is inconsistency between studies, and relative risks were all small.There has been much speculation about the role of certain viruses in human brain tumours (Barbanti-Brodano et al, 1997), but very few epidemiological studies have addressed the possibility of an infectious aetiology. If infections are involved in the aetiology of childhood brain tumours, the distribution of cases may be predicted to exhibit space -time clustering. Space -time clustering is said to occur when excess numbers of cases are observed within various small geographical locations, but only at limited points in time. The presence of seasonal variation would also provide evidence for an infectious aetiology. We have therefore examined incidence data from the Manchester Children's Tumour Registry (MCTR) for presence of space -time clustering and seasonal variation. This registry is population based with consistently high ascertainment and contains verified diagnostic data over a 45 year period (Birch, 1988). The aims of our study were to test predictions of space -time clustering and seasonal patterns which might arise as a result of infectious mechanisms and to distinguish between exposures around the times of birth ...

Summary Infection has long been suspected as a possible factor in the aetiology of leukaemia and lymphoma. If seasonal variation in the onset of disease could be shown in any of the diagnostic subgroups of leukaemia or tymphoma, this would provide supportive evidence of an aetiology linked to exposure to infection. All cases in the Manchester Children's Tumour Registry (aged 0-14 years at diagnosis) with acute tymphoblastic leukaemia (ALL), acute non-lymphocytic leukaemia (ANLL), Hodgkin's disease (HD) or non-Hodgkin Iymphoma (NHL) between 1 January 1954 and 31 December 1996 were included in an analysis of seasonal variation in the month of first symptom and the month of diagnosis. Cases of common acute lymphoblastic leukaemia (c-ALL) diagnosed from 1979 onwards were also analysed separately. The groups considered for analysis were: all cases of ALL (n = 1070), ALL diagnosed between 18 and 95 months of age (n = 730), ALL diagnosed over 95 months of age (n = 266), c-ALL (n = 309), ANLL (n = 244), all infant acute leukaemias (ALL and ANLL under 18 months: n = 107), HD (n = 166) and NHL (n = 189). Using the Edwards method, both c-ALL and HD demonstrated significant seasonal variation (P = 0.037 and 0.001 respectively) in date of first symptom, with peaks occurring in November and December respectively. Using this method, no indication of seasonal variation was found in the other diagnostic groups for date of first symptom or in any of the diagnostic groups for date of diagnosis. For comparison with a previous study, a further analysis based on date of diagnosis for all ALL cases, using summer-winter ratios.showed a significant summer excess. These results provide supportive evidence for an infectious aetiology for c-ALL and HD. and possibly for all ALL, which warrants further investigation. Keywords: childhood cancer; leukaemia; lymphoma; season; epidemiology; infections Infection has long been suspected as a possible factor in the aetiology of leukaemia (Kellett, 1937). a possibility supported by recent york (Greaves. 1988: Kinlen. 1988: 1995 Correspondence to: JM Birch prox iding possible support for an infectious aetiology for this condition (Badrinath et al. 1997).Given the current interest in the possible aetiological role of infections. we have performed a comprehensix e study of studied seasonal variation The Manchester Children's Tumour Registrx (MCTR) (Blair and Birch. 1994) has high-qualits populationbased data in sufficient quantity to enable the use of powerful statistical techniques. We therefore hoped to achieve a more reliable assessment of anv seasonal fluctuations in onset. MATERIALS AND METHODSCases for the studv w-ere ascertained from the MCTR.